Many of the current major therapeutic problems require treatment of the brain. This includes neurodegenerative diseases such as Parkinson and Alzheimer diseases, but also central nervous system diseases such as schizophrenia, epilepsy and bipolar disorder. Also brain cancer, human immunodeficiency virus (HIV) and even certain aspects of obesity as pharmaceutical targets located inside the brain can be included. In many cases there are promising compounds for their treatment, however owing to their BBB transport problems more than 98% of these potential drugs do not go to development stage.
The BBB is a natural filter within the body that only allows certain substances through from the blood to the brain. It is a natural defense mechanism designed to keep harmful substances out of the brain. It controls the composition of the brain extracellular fluid independent of fluctuations within the blood. It is also impermeable for many environmental compounds and drugs.
The anatomical basis of the BBB is primarily the tight junction at endothelial cells of cerebral microvessels. Cerebral microvessels form a continuous membrane with no fenestrations and the tight junctions between them are responsible for a high transendothelial electrical resistance. Specific transporters mediate the access of certain molecules important for the brain, such as glucose, isolated amino acids and ions. Other compounds or drugs are dependent on diffusion through the lipid bilayers of the endothelial membranes which requires a certain degree of lipophilicity of these compounds.
There are different therapeutical fields where there is a need to find new drugs that can cross the BBB to arrive to its target site. For instance, the brain might serve as an occult reservoir for human immunodeficiency virus (HIV) viral replication. HIV in the brain and in the cerebro-spinal fluid may be particularly resistant to chemotherapy because of the failure of anti-retroviral drugs to penetrate the BBB. The virus can cross the BBB either during primary infection or at a later stage. The resulting infection leads to a number of central-nervous system disorders such as acquired immunodeficiency syndrome (AIDS) dementia complex and HIV encephalopathy.
Brain cancer can be counted among the most deadly and intractable diseases. Presently the treatment of brain cancer consist on surgery, radiation therapy using high-energy X-rays or other types of radiation and chemotherapy using anti-cancer or cytotoxic drugs. These anticancer drugs can reach cancer cells wherever they are in the body, but in the case of brain tumors not all chemotherapy drugs are suitable, because most of them cannot cross the blood-brain barrier (cf. D. Fortin et al., “Enhanced chemotherapy delivery by intraarterial infusion and blood brain barrier disruption in malignant brain tumors”, Cancer 2005, vol. 103, pp. 2606-15).
Another field of interest is psychiatric diseases, such as schizophrenia. Schizophrenia affects about 1% of the population. Although anti-psychotic drugs are been used, there is a need to find new and better drugs without the undesired side effects of the existing ones. In the search of these novels drugs the BBB is the barrier that the drug will need to cross to arrive to its target site.
Another field of interest is neurodegenerative diseases, such as Parkinson disease. Parkinson's disease is one of the major neurodegenerative disorders, affecting 3% of the population over the age of 65. Currently there is no preventive therapy for Parkinson's disease. The actual treatment consist of improving the motor symptoms by supplementation of the deficient neurotransmitter dopamine. As dopamine does not cross the BBB, a precursor of dopamine, L-dopa, has been used in the treatment of Parkinson disease since the 1960's. However, severe side effects are frequently observed within a few years of L-dopa therapy. L-dopa crosses the BBB using an amino acid transporter and once inside it is transformed to dopamine by the aromatic L-amino acid descarboxylase.
Finally, another field of interest is epilepsy, a syndrome of episodic brain dysfunction that affects about 1% of the general population. About 30% of epilepsies are classified as symptomatic since they are associated with an identifiable central nervous system injury, while the rest of them do not have identified causes. Current medical therapy of epilepsy is largely symptomatic and it is aimed at controlling seizures in affected individuals. If antiepileptic drugs fail, a temporal lobectomy, an operation which involves removing the region of the brain from which the seizures originates, provides an alternative treatment. This operation is highly successful in most cases, but fails in some, and moreover many individuals are reluctant to undergo surgery that involves removing parts of the brain.
In all these cases, many promising compounds are known for their treatment, however, owing to their BBB transport problems, they are not further developed. Research in these fields have taken several approaches. Some methods of administration of drugs to the brain either for therapy or diagnosis are invasive techniques, such as intracranial administration, administration altering BBB integrity or osmotic disruption. Other methods of administration of drugs to the brain have undesired side effects derived from the administration at high doses.
Another approach is drug modification. These modifications include for instance reduction of drug size or increase of drug lipophylicity, but it is not always possible to introduce such modifications. In the case of introducing an irreversible modification it is necessary that it does not alter the drug activity once it gets to the target site. In the case of a bioreversible modification, it is necessary to find an enzymatic or chemical process that will recover the active drug once the prodrug is inside the central nervous system.
Another approach is the administration by conjugation to a biological carrier. This strategy use monoclonal antibodies that bind to the transferrin receptor and undergo receptor mediated endocytosis, as molecular trojan horses of compounds with a therapeutical use that can not cross the BBB by themselves.
Thus despite all the research efforts invested in the past, there is still an important need to find substances having pharmacologically or diagnostic utility that can cross the BBB.